We focus on 3 themes integral to induction, mechanisms and inhibition of pathogenesis of sickle cell crises. 1) Rheology: HbS gels are solid-like and viscoelastic. Their rheology and potential for microvascular obstruction depend on HbS fiber mechanics, which we have characterized, and fiber cross-linking. We will characterize gel elasticity, viscosity and yield strengths and relate these to fiber mechanics. We will also measure interfiber forces responsible for cross-linking. 2) Kinetics & equilibria: Gelatin kinetics are critical for pathogenesis because of the highly variable nucleation dependent delay time. We seek to identify the site of heterogeneous nucleation of new fibers on pre-existing ones and part of the delay time. The possibility that new fibers may arise from fiber defects will be studied. Contributions of component parts of delay time, including a delay that depends on the critical level of rheology, will be measured. Their mutability will be examined with the aim of inhibiting pathogenesis by increasing the delay. Energetics of the incorporation of hemoglobin A into the polymer, relevant to mutant site interactions, will be studied. 3) Depolymerization: Since depolymerization rates and mechanisms may contribute to pathology, a possibility previously little considered, we will continue to characterize this process, including the fiber elongation 'on' and 'off' rates and the mechanism and rates of the second mechanism of depolymerization we have identified, rapid depolymerization from fiber sides. Finally, we will study the rates and mechanisms of depolymerization of domains, the basic units within gels.